title: The tumor suppressor activity of the transmembrane protein with epidermal growth factor and two follistatin motifs 2 (TMEFF2) correlates with its ability to modulate sarcosine levels.
abstract: The type I transmembrane protein with epidermal growth factor and two follistatin motifs 2 (TMEFF2) is expressed in brain and prostate and overexpressed in prostate cancer, but its role in this disease is unclear. Several studies have suggested that TMEFF2 plays a role in suppressing the growth and invasive potential of human cancer cells, whereas others suggest that the shed portion of TMEFF2, which lacks the cytoplasmic region, has a growth-promoting activity. Here we show that TMEFF2 has a dual mode of action. Ectopic expression of wild-type full-length TMEFF2 inhibits soft agar colony formation, cellular invasion, and migration and increases cellular sensitivity to apoptosis. However, expression of the ectodomain portion of TMEFF2 increases cell proliferation. Using affinity chromatography and mass spectrometry, we identify sarcosine dehydrogenase (SARDH), the enzyme that converts sarcosine to glycine, as a TMEFF2-interacting protein. Co-immunoprecipitation and immunofluorescence analysis confirms the interaction of SARDH with full-length TMEFF2. The ectodomain does not bind to SARDH. Moreover, expression of the full-length TMEFF2 but not the ectodomain results in a decreased level of sarcosine in the cells. These results suggest that the tumor suppressor activity of TMEFF2 requires the cytoplasmic/transmembrane portion of the protein and correlates with its ability to bind to SARDH and to modulate the level of sarcosine.
authors.affiliation: Department of Biochemistry and Molecular Biology, Brody School of Medicine, Greenville, North Carolina 27834, USA.
authors.forename: Xiaofei
authors.initials: X
authors.lastname: Chen
authors.forename: Ryan
authors.initials: R
authors.lastname: Overcash
authors.forename: Thomas
authors.initials: T
authors.lastname: Green
authors.forename: Donald
authors.initials: D
authors.lastname: Hoffman
authors.forename: Adam S
authors.initials: AS
authors.lastname: Asch
authors.forename: Maria J
authors.initials: MJ
authors.lastname: Ruiz-Echevarría
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D005998:Glycine / Q000235:genetics / Q000378:metabolism; D057809:HEK293 Cells; D006801:Humans; D008297:Male; D008565:Membrane Proteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D041681:NIH 3T3 Cells; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D012521:Sarcosine / Q000235:genetics / Q000378:metabolism*; D050892:Sarcosine Dehydrogenase / Q000235:genetics / Q000378:metabolism*; D025521:Tumor Suppressor Proteins / Q000235:genetics / Q000378:metabolism*
chemical_list: D008565:Membrane Proteins; D009363:Neoplasm Proteins; C423567:TMEFF2 protein, human; D025521:Tumor Suppressor Proteins; C494395:SARDH protein, human; D050892:Sarcosine Dehydrogenase; D005998:Glycine; D012521:Sarcosine